Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
Neurobiol Dis. 2022 Jul;169:105745. doi: 10.1016/j.nbd.2022.105745. Epub 2022 May 2.
Neonatal inflammation can increase the risk of anxiety disorder in adulthood. The balance between glutamatergic excitatory and GABAergic inhibitory transmissions in the basolateral amygdala (BLA) plays a vital role in controlling anxiety state. Based on the reports that early-life inflammation had adverse effects on GABAergic system, the aim of this study was to investigate whether and how neonatal inflammation affects excitatory-inhibitory circuits in the BLA resulting in anxiety disorder. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3-5. LPS-treated mice developed anxiety behaviors accompanied by the hyperactivity of adrenal axis in adulthood. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-BLA excitatory synapses of LPS mice which could be recovered by bath-application of GABAR agonist suggesting the impairment of GABAergic system in LPS mice. Compared with controls, GABARα2 subunit expression and density of GABA-evoked current in BLA principal neurons were reduced in LPS mice. Additionally, neonatal LPS treatment resulted in the down-regulation of transforming growth factor-beta 1 (TGF-β1) expression and PKC signaling pathway in the adult BLA. The local TGF-β1 overexpression in the BLA improved GABARα2 expression via up-regulating the activity of PKC signaling, which corrected GABAR-mediated inhibition leading to the abolishment of anxiety-like change in adrenal axis regulation and behaviors in LPS mice. These data suggest the persistent TGF-β1deficit induces the down-regulation of GABARα2 expression and subsequent disruption of the excitation-inhibition balance in the BLA circuits, which is the important mechanisms of neonatal inflammation-induced anxiety disorder.
新生儿炎症会增加成年后患焦虑症的风险。外侧杏仁核（BLA）中的谷氨酸能兴奋性和 GABA 能抑制性传递之间的平衡对于控制焦虑状态起着至关重要的作用。基于早期生命炎症对 GABA 能系统有不良影响的报告，本研究旨在探讨新生儿炎症是否以及如何影响 BLA 中的兴奋性-抑制性回路，从而导致焦虑症。新生小鼠在出生后第 3-5 天每天接受脂多糖（LPS，50μg/kg）或生理盐水皮下注射。LPS 处理的小鼠在成年后表现出焦虑行为，同时伴有肾上腺轴的过度活跃。电生理研究显示，LPS 小鼠皮质-BLA 兴奋性突触后神经元兴奋性增加，而 GABA 能激动剂的浴应用可恢复这种兴奋性增加，提示 LPS 小鼠的 GABA 能系统受损。与对照组相比，LPS 小鼠 BLA 主神经元中的 GABARα2 亚基表达和 GABA 诱发电流密度降低。此外，新生 LPS 处理导致成年 BLA 中转化生长因子-β1（TGF-β1）表达和 PKC 信号通路下调。BLA 中局部 TGF-β1 过表达通过上调 PKC 信号通路活性来提高 GABARα2 表达，从而纠正 GABAR 介导的抑制作用，导致 LPS 小鼠在肾上腺轴调节和行为方面的焦虑样变化消失。这些数据表明，持续的 TGF-β1 缺乏会导致 GABARα2 表达下调，随后破坏 BLA 回路中的兴奋-抑制平衡，这是新生儿炎症引起焦虑症的重要机制。
